Novel anthranilamide pyridinureas as vascular endothelial growth factor (vegf) receptor kinase inhibitors

ABSTRACT

The invention relates to novel anthranilamide pyridinureas as VEGF receptor kinase inhibitors, their production and use as pharmaceutical agents for preventing or treating diseases that are triggered by persistent angiogenesis.

This application claims the benefit of the filing date of U.S.Provisional Application Ser. No. 60/626,914 filed Nov. 12, 2004 which isincorporated by reference herein.

The invention relates to novel anthranilamide pyridinureas as VEGFreceptor kinase inhibitors, their production and use as pharmaceuticalagents for preventing or treating diseases that are triggered bypersistent angiogenesis.

Many diseases are known to be associated with persistent angiogenesis,for example, diseases such as tumor- or metastases-growth; psoriasis;arthritis, such as rheumatoid arthritis, hemangioma, endometriosis,angiofibroma; eye diseases, such as diabetic retinopathy, neovascularglaucoma; renal diseases, such as glomerulonephritis, diabeticnephropathy, malignant nephrosclerosis, thrombotic microangiopathicsyndrome, transplant rejections and glomerulopathy; fibrotic diseases,such as cirrhosis of the Liver, mesangial cell proliferative diseasesand arteriosclerosis.

Lymphangiogenesis is a process accompanying tumor growth and metastases.It is prominent in lymphedema, lymphangiectasia, lymphangioma, andlymphangiosarcoma and in asthmatic disease, where lymph vessels arechronically overexpressed in the lung.

Persistent angiogenesis is induced by the factor VEGF via its receptors.In order for VEGF to exert this action, it is necessary that VEGF bindto the receptor, and that a tyrosine phosphorylation is induced.

Direct or indirect inhibition of the VEGF receptor can be used forpreventing or treating such diseases and other VEGF-induced pathologicalangiogenesis and vascular permeable conditions, such as tumorvascularization. For example, it is known that the growth of tumors canbe inhibited by soluble receptors and antibodies against VEGF, anexample for the latter being Avastin® whose treatment paradigm has beenintroduced in human cancer therapy.

Anthranilic acid amides effective in the treatment of psoriasis;arthritis, such as rheumatoid arthritis, hemangioma, angiofibroma; eyediseases, such as diabetic retinopathy, neovascular glaucoma; renaldiseases, such as glomerulonephritis, diabetic nephropathy, malignantnephrosclerosis, thrombic microangiopathic syndrome, transplantrejections and glomerulopathy; fibrotic diseases, such as cirrhosis ofthe liver, mesangial cell proliferative diseases, arteriosclerosis,injuries to nerve tissue, and for inhibiting the reocclusion of vesselsafter balloon catheter treatment, in vascular prosthetics or aftermechanical devices are used to keep vessels open, such as, e.g., stents,have is been reported in WO 00/27820.

Anthranilic acid amides that are effective in the treatment of tumor ormetastasis growth, psoriasis, Kaposi's sarcoma, restenosis, such as,e.g., stent-induced restenosis, endometriosis, Crohn's disease,Hodgkin's disease, leukemia; arthritis, such as rheumatoid arthritis,hemangioma, angiofibroma;

eye diseases, such as diabetic retinopathy, neovascular glaucoma; renaldiseases, such as glomerulonephritis, diabetic nephropathy, malignantnephrosclerosis, thrombic microangiopathic syndrome, transplantrejections and glomerulopathy; fibrotic diseases, such as cirrhosis ofthe liver, mesangial cell proliferative diseases, arteriosclerosis,injuries to nerve tissue, and for inhibiting the reocclusion of vesselsafter balloon catheter treatment, in vascular prosthetics or aftermechanical devices are used to keep vessels open, such as, e.g., stents,as immunosuppressive agents, as a support in scar-free healing, insenile keratosis and in contact dermatitis have also been reported in WO04/13102.

There is, however, a desire to produce compounds that are as efficaceousas possible in as broad a range of indications as possible. A constantblockade of VEGF mediated signal transduction is desirable in order toreduce persistant angiogenesis and lymphangiogenesis. Suitable compoundsfor longer term treatment should exhibit little or no drug-druginteraction potential. The Cytochrome P450 isoenzymes play a pivotalrole in the degradation of pharmaceutical agents. The problem is alsocomplicated by the fact that patients may express different relativeamounts of the isoenzymes. An inhibition of these isoenzymes may resultin undesirable pharmaceutical agent interactions, especially in the caseof multimorbid patients (patients with multiple disease conditions). Forexample, inhibition of the Cytochrome P450 isoenzymes responsible formetabolisation of the parent agent could lead to toxic systemicconcentrations. A further problem exists in combination therapy withother medications, whereby inhibition of the Cytochrome P450 isoenzymesresponsible for metabolising the co-medications could lead to toxicsystemic concentrations of the co-medication. This is especially thecase for co-administered cytostatics in the case of cancer therapy.

Thus, it has now surprisingly been found that compounds of generalformula (I), as described below, have more advantageous physico-chemicaland/or pharmacokinetic properties and prevent, for example, tyrosinephosphorylation or stop persistent angiogenesis and thus the growth andpropagation of tumors, whereby they are distinguished in particular by apotent inhibition of VEGF receptor kinases and a reduced potential fordrug-drug interactions, specifically a reduced inhibition of cytochromeP450 isoenzymes 2C9 and 2C19.

The compounds of formula (I) are thus suitable, for example, for thetreatment or prevention of diseases for which an inhibition ofangiogenesis and/or the VEGF receptor kinases is beneficial.

In one aspect of the invention, there is provided an anthranilamidepyridinurea compound of formula (I):

wherein:

X is CH or N, preferably CH;

is hydrogen or fluorine; preferably hydrogen;

A, E and Q independently of one another, are CH or N, whereby only a tomaximum of two nitrogen atoms are contained in the ring; preferably A,E, and Q are each CH;

R¹ is aryl or heteroaryl, which may be optionally substituted in one ormore places in the same way or differently with halogen, hydroxy,C₁-C₁₂-alkyl, C₂-C₆-alkenyl, C₁-C₁₂-atkoxy, halo-C₁-C₆-alkyl, ═O,—SO₂R⁶, —OR⁵, —SOR⁴, —COR⁶, —CO₂R⁶ or —NR⁷R⁸, whereby C₁-C₁₂-alkyl maybe substituted with —OR⁵ or —NR⁷R⁸, with the proviso that when R² and R³are both —CH₃, R¹ is not any one of the following:

-   -   preferably heteroaryl optionally substituted in one or more        places in the same way or differently with halogen, hydroxy,        C₁-C₁₂-alkyl, C₂-C₆-alkenyl, C₁-C₁₂-alkoxy, halo-C₁-C₆-alkyl,        ═O, —SO₂R⁶, —OR⁵, —SOR⁴, —COR⁶, —CO₂R⁶ or —NR⁷R⁸, whereby        C₁-C₁₂-alkyl may be substituted with —OR⁵ or —NR⁷R⁸, with the        proviso that when R² and R³ are both —CH₃, R¹ is not any one of        the following:

-   -   more preferably heteroaryl substituted in one or more places in        the same way or differently with halogen, hydroxy, C₁-C₁₂-alkyl,        C₂-C₆-alkenyl, C₁-C₁₂-alkoxy, halo-C₁-C₆-alkyl, ∇O, —SO₂R⁶,        —OR⁵, —SOR⁴, —COR⁶, —CO₂R⁶ or —NR⁷R⁸, whereby C₁-C₁₂-alkyl may        be substituted with —OR⁵ or —NR⁷R⁸, with the proviso that when        R² and R³ are both —CH₃, R¹ is not any one of the following:

-   -   even more preferably R¹ is

-   -   wherein R⁹ is hydrogen, halogen, C₁-C₁₂-alkyl, C₁-C₁₂-alkoxy,        halo-C₁-C₆-alkyl, —COR⁶, —CO₂R⁶ or —NR⁷R⁸, whereby C₁-C₁₂-alkyl        may be substituted with —OR⁵ or —NR⁷R⁸ and R¹⁰ is hydrogen or        halogen; preferably R⁹ is hydrogen and R¹⁰ is hydrogen or        halogen, preferably fluorine; more particularly preferably R⁹        and R¹⁰ are both hydrogen;    -   more particularly preferably R¹ is

-   -   wherein R⁹ is hydrogen, halogen, C₁-C₁₂-alkyl, C₁-C₁₂-alkoxy,        halo-C₁-C₆-alkyl, —COR⁶, —CO₂R⁶ or —NR⁷R⁸, whereby C₁-C₁₂-alkyl        may be substituted with —OR⁵ or —NR⁷R⁸, more particularly        preferably R⁹ is hydrogen;

R² and R³, independently of one another, are C₁-C₁₂ alkyl optionallysubstituted with —OR⁵; preferably C₁-C₂ alkyl optionally substitutedwith —OR⁵; more preferably unsubstituted C₁-C₂ alkyl; more particularlypreferably are both —CH₃;

R⁴ is C₁-C₁₂-alkyl, C₃-C₈-cycloalkyl, aryl or heteroaryl; preferablyC₁-C₁₂-alkyl; more particularly preferably —CH₃;

R⁵ is hydrogen, C₁-C₁₂-alkyl, C₃-C₈-cycloalkyl or halo-C₁-C₆-alkyl;preferably —CH₃ or hydrogen; more particularly preferably hydrogen;

R⁶ is hydrogen, C₁-C₁₂-alkyl, C₃-C₈-cycloalkyl, halo-C₁-C₆-alkyl, aryl,or —NR⁷R⁸; preferably C₁-C₁₂-alkyl or —NR⁷R⁸; more particularlypreferably —CH₃;

R⁷ and R⁸, independently of one another, are hydrogen, —SO₂R⁶, —COR⁶,aryl, C₃-C₈-cycloalkyl, C₁-C₁₂-alkyl, halo-C₁-C₁₂-alkyl, orC₁-C₁₂-alkoxY, whereby C₁-C₁₂-alkyl may be optionally substituted with—OR⁵ or —N(CH₃)₂, or R⁷ and R⁸ may also be chosen in such a way as toprovide a 3-8 membered cycloalkyl ring, preferably a 4-7 memberedcycloalkyl ring, more preferably a 5 or 6 membered cycloalkyl ring,which may optionally contain further heteroatoms, such as nitrogen,oxygen or sulphur, and may be optionally substituted in one or morepositions in the same way or differently with halogen, cyano,C₁-C₁₂-alkyl, C₁ -C₁₂-alkoxy, halo-C₁-C₆-alkyl, ═O, —OR⁵ , COR⁶, —SR⁴,—SOR⁴ or —SO₂R⁶; preferably R⁷ and R⁸ independently of one another, arehydrogen, COR⁶, —SO₂R⁶, alkyl; more preferably hydrogen or C₁-C₁₂-alkyl;more particularly preferably hydrogen or —CH₃,

and as well as isomers, diastereoisomers, enantiomers, tautomers andsalts thereof.

In a second aspect of the present invention, there is provided apharmaceutical agent comprising at least one compound of formula (I) oran isomer, diastereoisomer, enantiomer, tautomer or salt thereof.

In a third aspect of the present invention, there is provided apharmaceutical agent comprising at least one compound of formula (I) oran isomer, diastereoisomer, enantiomer, tautomer or salt thereof and atleast one pharmaceutically acceptable carrier, diluent or excipient.

In a fourth aspect of the present invention, there is provided apharmaceutical agent comprising at least one compound of formula (I) oran isomer, diastereoisomer, enantiomer, tautomer or salt thereof for usein the prevention or treatment of diseases associated with persistantangiogenesis and/or diseases associated with excessivelymphangiogenesis.

In a fifth aspect of the present invention, there is provided apharmaceutical agent comprising at least one compound of formula (I) oran isomer, diastereoisomer, enantiomer, tautomer or salt thereof for usein the prevention or treatment of tumor- or metastases-growth;psoriasis; Karposi's sarcoma; restenosis including stent-inducedrestenosis; Crohn's disease; Hodgkin's disease; leukemia; arthritisincluding rheumatoid arthritis, hemangioma, angiofibroma; endometriosis;eye diseases including diabetic retinopathy, neovascular glaucoma;corneal transplants; renal diseases, including glomerulonephritis,diabetic nephropathy, malignant nephrosclerosis, thromboticmicroangiopathic syndrome, transplant rejections and glomerulopathy;fibrotic diseases, including cirrhosis of the liver; mesangial cellproliferative diseases; arteriosclerosis; injuries to the nerve tissue,and for inhibiting the reocclusion of vessels after balloon cathetertreatment; in vascular prosthetics or after mechanical devices are usedto keep vessels open, as immunosuppresive agent for supporting scar-freehealing; senile keratosis; contact dermatitis; and asthma.

In a sixth aspect of the present invention, there is provided apharmaceutical agent comprising at least one compound of formula (I) oran isomer, diastereoisomer, enantiomer, tautomer or salt thereof for useas VEGF receptor kinase 3-inhibitors of lymphangiogenesis.

In a seventh aspect of the present invention, there is provided apharmaceutical agent comprising at least one compound of formula (I) oran isomer, diastereoisomer, enantiomer, tautomer or salt thereof for usein a method for the treatment of the human or animal body.

In an eighth aspect of the present invention, there is provided apharmaceutical agent comprising at least one compound of formula (I) oran isomer, diastereoisomer, enantiomer, tautomer or salt thereof for usein the preparation of a pharmaceutical product for the prevention ortreatment of a disease for which an inhibition of angiogenesis and/orlymphangiogenesis and/or the VEGF receptor kinases is beneficial.

In a ninth aspect of the present invention, there is provided apharmaceutical agent comprising at least one compound of formula (I) oran isomer, diastereoisomer, enantiomer, tautomer or salt thereof for useas an inhibitor of the tyrosine kinases VEGFR-1 and VEGFR-2.

In a tenth aspect of the present invention, there is provided a compoundof general formula (III):

in which A, E, Q, W, X, R² and R³, are as defined for formula (I) supraand R^(y) is H or C₁-C₆-alkyl, as intermediate for the preparation of acompound of formula (I). Preferably W is H or C₁-C₂-alkyl, W is hydrogenand X is CH; more preferably R^(y) is H or —CH₃, W is hydrogen and X isCH.

In an eleventh aspect of the present invention, there is provided theuse of a compound of general formula (III), in which A, E, Q, W, X, R²and R³ are as defined for formula (I) supra and R^(y) is H orC₁-C₆-alkyl, as intermediate for the preparation of a compound offormula (I).

In a twelfth aspect of the present invention, there is provided aprocess for the preparation of a compound of formula (I), wherein allsubstituents are as is described in claim 1, in which a compound offormula (III), wherein A, E, Q, W, X, R² and R³ are as defined in claim1 and R^(y) is H or C₁-C₆-alkyl, is reacted with an amine of formulaR¹NH₂ in which R¹ is as defined in claim 1.

In a thirteenth aspect of the present invention, there is provided aprocess for the preparation of a compound of formula (I), wherein allsubstituents are as described in claim 1, in which a compound of formula(II):

wherein A, E, Q, W, X, and R¹ are as defined in claim 1 and M stands forhalogen, is:

(i) first converted to an amine and subsequently converted to a compoundof formula (I) by reaction with a carbamoyl chloride of formulaClCONR²R³, wherein R² and R³ are as defined in claim 1; oralternatively,

(ii) reacted with a compound of formula H₂NCONR²R³, wherein R² and R³are as defined in claim 1, or alternatively,

(iii) first converted to an amine and subsequently converted to acompound of formula (I) by first reacting with a compound of formulaClCO₂Ph and then reacting with a compound of formula HNR²R³, wherein R²and R³ are as defined in claim 1. Preferably a compound of formula (I)is prepared using the (ii) process.

As used herein, the term “alkyl” is defined in each case as asubstituted or zo unsubstituted straight-chain or branched alkyl group,such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tert-butyl, pentyl, isopentyl or hexyl, heptyl, octyt, nonyl, decyl,undecyl, or dodecyl.

As used herein, the term “alkoxy” is defined in each case as astraight-chain or branched alkoxy group, such as, for example,methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy,tert-butyloxy, pentyloxy, isopentyloxy, hexyloxy, heptyloxy, octyloxy,nonyloxy, decyloxy, undecyloxy or dodecyloxy.

As used herein, the term “cycloalkyl” is defined as a monocyclic alkylring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, orcycloheptyl, cyclooctyl, cyclononyt or cyclodecyl, and also as bicyclicrings or tricyclic rings, such as, for example, adamantanyl. Thecycloalkyl group may also contain, one or more heteroatoms, such asoxygen, sulphur and/or nitrogen, such that a heterocycloalkyl ring isformed.

As used herein, the term “halogen” is defined in each case as fluorine,chlorine, bromine or iodine, with fluorine being preferred for compoundsof formula (I ) and chlorine and bromine being preferred as substituentM in compounds of formula (II).

As used herein, the term “halo-C₁-C₆-alkyl” is defined as a C₁-C₆ alkylgroup wherein some or all hydrogen atoms are replaced by halogen atoms,preferably replaced with fluoro atoms. Preferred is the group CF₃.

As used herein, the term “alkenyl” is defined in each case as astraight-chain or branched alkenyl group that contains 2-6, preferably2-4 carbon atoms. For example, the following groups can be mentioned:vinyl, propen-1-yl, propen-2-yl, but-1-en-1 -yl, but-1-en-2-yl,but-2-en-1-yl, but-2-en-2-yl, 2-methyl-prop-2-en-1-yl,2-methyl-prop-1-en-1-yl, but-1-en-3-yl, but-3-en-1-yl, and allyl.

As used herein, the term “aryl” is defined in each case has 6-12 carbonatoms, such as, for example, cyclopropenyl, cyclopentadienyl, phenyl,tropyl, cyclooctadienyl, indenyl, naphthyl, azulenyl, biphenyl,fluorenyl, anthracenyl etc, phenyl being preferred.

As used herein, the term “C₁-C₁₂”, as used throughout this text e.g. inthe context of the definitions of “C₁-C₁₂-alkyl” and “C₁-C₁₂-alkoxy”, isto be understood as meaning an alkyl or alkoxy group having a finitenumber of carbon atoms of 1 to 12, i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11 or 12 carbon atoms. It is to be understood further that said term“C₁-C₁₂” is to be interpreted as any subrange comprised therein, e.g.C₁-C₁₂, C₂-C₁₁, C₃-C₁₀, C₄-C₉, C₅-C₈, C₆-C₇, C₁-C₂, C₁-C₃, C₁-C₄, C₁-C₅,C₁-C₆, C₁-C₇, C₁-C₈, C₁-C₉, C₁-C₁₀, C₁-C₁₁; preferably C₁-C₂, C₁-C₃,C₁-C₄, C₁-C₅, C₁-C₆; more preferably C₁-C₃.

Similarly, as used herein, the term “C₂-C₆”, as used throughout thistext e.g. in the context of the definitions of “C₂-C₆-alkenyl”, is to beunderstood as meaning an alkenyl group having a finite number of carbonatoms of 2 to 6, i.e. 2, 3, 4, 5, or 6 carbon atoms. It is to beunderstood further that said term “C₂-C₆” is to be interpreted as anysubrange comprised therein, e.g. C₂-C₆, C₃-C₅, C₃-C₄, C₂-C₃, C₂-C₄,C₂-C₅; preferably C₂-C₃.

Further as used herein, the term “C₁-C₆”, as used throughout this texte.g. in the context of the definitions of “halo-C₁-C₆-alkyl”, is to beunderstood as meaning a haloalkyl group having a finite number of carbonatoms of 1 to 6, i.e. 1, 2, 3, 4, 5, or 6 carbon atoms. It is to beunderstood further that said term “C₁-C₆” is to be interpreted as anysubrange comprised therein, e.g. C₁-C₆, C₂-C₅, C₃-C₄, C₁-C₂, C₁-C₃,C₁-C₄, C₁-C₅, C₁-C₆; more preferably C₁-C₃.

As used herein, the term “heteroaryl” as defined in each case, is anaromatic ring system which contains, in the ring, at least oneheteroatom which may be identical or different, and which comprises 3-16ring atoms, preferably 5 or 6 atoms, more preferably 9 or 10 ring atoms,said heteroatom being such as oxygen, nitrogen or sulphur, and can bemonocyclic, bicyclic, or tricyclic, and in addition in each case can bebenzocondensed. Preferably heteroaryl is selected from thienyl, furanyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc., and benzoderivatives thereof, such as, e.g., benzofuranyl, benzothienyl,benzoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl,isoindolyl, etc.; or pyridyt, pyridazinyl, pyrimidinyl, pyrazinyl,triazinyl, etc., and benzo derivatives thereof, such as, e.g.,quinolinyl, isoquinotinyl, etc.; or azocinyl, indolizinyl, purinyl,etc., and benzo derivatives thereof; or cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, naphthpyridinyt, pteridinyl, carbazolyl,acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl, oroxepinyl, etc. More preferably the heteroaryl is selected fromindazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, benzotriazolyl.Particularly preferably, the heteroaryl is indazolyl.

The aryl group and the heteroaryl group in each case can be substitutedin the same way or differently in one or more positions with halogen,hydroxy, C₁-C₁₂-alkyl, C₂-C₆-alkenyl, C₁-C₁₂-alkoxy, halo-C₁-C₆-alkyl,═O, —SO₂R⁶, —OR⁵, —SOR⁴, —COR⁶, —CO₂R⁶ or —NR⁷R⁸, whereby C₁-C₁₂-alkylmay be substituted with —OR⁵ or —NR⁷R⁸. It is understood that thesubstitution on the aryl group and the heteroaryl group may take placeon any one of the group's carbon atoms and/or on any one of theheteroatoms. Preferably, the aryl group and the heteroaryl group issubstituted in one or two positions.

If an acid group is included, the physiologically compatible salts oforganic and inorganic bases are suitable as salts, such as, for example,the readily soluble alkali salts and alkaline-earth salts as well asN-methyl-glucamine, dimethyl-glucamine, ethyl-glutamine, lysine,1,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol,tris-hydroxy-methyl-amino-methane, aminopropanediol, Sovak base, and1-amino-2,3,4-butanetriol.

If a basic group is included, the physiologically compatible salts oforganic and inorganic acids are suitable, such as hydrochloric acid,sulphuric acid, phosphoric acid, citric acid, tartaric acid, succinicacid, fumaric acid, etc.

The compounds of general formula (I) according to the invention alsocontain the possible tautomeric forms and comprise the E-isomers orZ-isomers, or, if one or more stereogenic centers are present, racematesand/or enantiomers and/or diastereoisomers. Thus, a molecule with asingle stereogenic center may be a mixture of enantiomers (R,S), or maybe a single (R) or (S) enantiomer. A molecule with more than onestereogenic centre may be a mixture of diastereoisomers, or may be asingle diastereoisomer, whereby the diastereoisomers may also exist asmixtures of enantiomers or single enantiomers.

One embodiment of the present invention are compounds of formula (I)wherein X is CH.

In one embodiment, W is hydrogen.

In one embodiment, A, E, and Q are each CH.

In one embodiment, X is CH, W is hydrogen, and A, E, and Q each are CH.

In one embodiment, R¹ is heteroaryl optionally substituted in one ormore places in the same way or differently with halogen, hydroxy,C₁-C₁₂-alkyl, C₂-C₆-alkenyl, C₁-C₁₂-alkoxy, halo-C₁-C₆-alkyl, ═O,—SO₂R⁶, —OR⁵, —SOR⁴, —COR⁶, —CO₂R⁶ or —NR⁷R⁸, whereby C₁-C₁₂-alkyl maybe substituted with —OR⁵ or —NR⁷R⁸, with the proviso that when R² and R³are both —CH₃, R¹ is not any one of the following:

In another embodiment, R¹ is heteroaryl substituted in one or moreplaces in the same way or differently with halogen, hydroxy,C₁-C₁₂-alkyl, C₂-C₆-alkenyl, C₁-C₁₂-alkoxy, halo-C₁-C₆-alkyl, ═O,—SO₂R⁶, —OR⁵, —SOR⁴, —COR⁶, —CO₂R⁶ or —NR⁷R⁸, whereby C₁-C₁₂-alkyl maybe substituted with —OR⁵ or —NR⁷R⁸, with the proviso that when R² and R³are both —CH₃, R¹ is not any one of the following:

In a preferred embodiment, R¹ is

wherein R⁹ is hydrogen, halogen, C₁ ⁻C₁₂ ⁻alkyl, C₁-C₁₂-alkoxy,halo-C₁-C₆-alkyl, —COR⁶, —CO₂R⁶ or —NR⁷R⁸, whereby C₁-C₁₂-alkyl may besubstituted with —OR⁵ or —NR⁷R⁸ and R¹⁰ is hydrogen or halogen.

In a more preferred embodiment, R¹ is

wherein R⁹ is hydrogen and R¹⁰ is hydrogen or halogen.

In an even more preferred embodiment, R¹ is

wherein R⁹ is hydrogen, halogen, C₁-C₁₂-alkyl, C₁-C₁₂-alkoxy,halo-C₁-C₆-alkyl, —COR⁶, —CO₂R⁶ or —NR⁷R⁸, whereby C₁-C₁₂-alkyl may besubstituted with —OR⁵ or —NR⁷R⁸;

In a more particularly preferred embodiment, R¹ is

wherein R⁹ is hydrogen.

In one embodiment, R² and R³, independently of one another, are C₁-C₂alkyl optionally substituted with —OR⁵. In a preferred embodiment, R²and R³, independently of one another, are unsubstituted C₁-C₂ alkyl. Ina more particularly preferred embodiment, R² and R³ are both —CH₃.

In one embodiment, R⁴ is C₁-C₁₂-alkyl. In a preferred embodiment, R⁴ is—CH₃.

In one embodiment, R⁵ is —CH₃ or hydrogen. In a preferred embodiment, R⁵is hydrogen.

In one embodiment, R⁶ is C₁-C₁₂-alkyl or —NR⁷R⁸. In a preferredembodiment, R⁶ is C₁-C₁₂-alkyl. In a more preferred embodiment, R⁶ is—CH₃.

In one embodiment, R⁷ and R⁸, independently of one another, arehydrogen, COR⁶, SO₂R⁶, C₁-C₁₂-alkyl. In a preferred embodiment, R⁷ andR⁸ independently of one another are hydrogen or —CH₃.

In one embodiment:

X is CH,

W is hydrogen,

A, E and Q each are CH,

R¹ is heteroaryl optionally substituted in one or more places in thesame way or differently with halogen, hydroxy, C₁-C₁₂-alkyl,C₂-C₆-alkenyl, C₁-C₁₂-alkoxy, halo-C₁-C₆-alkyl, ═O, —SO₂R⁶, —OR⁵, —SOR⁴,—COR⁶, —CO₂R⁶ or —NR⁷R⁸, whereby C₁-C₁₂-alkyl may be substituted with—OR⁵ or —NR⁷R⁸, with the proviso that when R² and R³ are both —CH₃, R¹is not any one of the following:

R² and R³, independently of one another, are C₁-C₂ alkyl optionallysubstituted with —OR⁵,

R⁴ is C₁-C₁₂-alkyl, C₃-C₈-cycloalkyl, aryl or heteroaryl,

R⁵ is hydrogen, C₁-C₁₂-alkyl, C₃-C₈-cycloalkyl or halo-C₁-C₆-alkyl,

R⁶ is hydrogen, C₁-C₁₂-alkyl, C₃-C₈-cycloalkyl, halo-C₁-C₆-alkyl, aryl,or —NR⁷R⁸,

R⁷ and R⁸, independently of one another, are hydrogen, —SO₂R⁶, —COR⁶,aryl, C₃-C₈-cycloalkyl, C₁-C₁₂-alkyl, halo-C₁-C₁₂-alkyl, orC₁-C₁₂-alkoxy, whereby C₁-C₁₂-alkyl may be optionally substituted with—OR⁵ or —N(CH₃)₂, or R⁷ and R⁸ may also be chosen in such a way as toprovide a 3-8 membered cycloalkyl ring, preferably a 4-7 memberedcycloalkyl ring, more preferably a 5 or 6 membered cycloalkyl ring,which may optionally contain further heteroatoms, such as nitrogen,oxygen or sulphur, and may be optionally substituted in one or moreplaces in the same way or differently with halogen, cyano, C₁-C₁₂-alkyl,C₁-C₁₂-alkoxy, halo-C₁-C₆-alkyl, ═O, —OR⁵ , COR⁶, —SR⁴, —SOR⁴ or —SO₂R⁶,and

as well as isomers, diastereoisomers, enantiomers, tautomers and saltsthereof.

In a preferred embodiment:

X is CH,

W is hydrogen,

A, E and Q each are CH,

R¹ is heteroaryl substituted in one or more places in the same way ordifferently with halogen, hydroxy, C₁-C₁₂-alkyl, C₂-C₆-alkenyl,C₁-C₁₂-alkoxy, halo-C₁-C₆-alkyl, ═O, —SO₂R⁶, —OR⁵, —SOR⁴, —COR⁶, —CO₂R⁶or —NR⁷R⁸, whereby C₁-C₁₂-alkyl may be substituted with —OR⁵ or —NR⁷R⁸,with the proviso that when R² and R³ are both —CH₃, R¹ is not any one ofthe following:

R² and R³ independently of one another, are C₁-C₂ alkyl. optionallysubstituted with —OR⁵;

R⁴ is C₁-C₁₂-alkyl, C₃-C₈-cycloalkyl, aryl or heteroaryl,

R⁵ is hydrogen, C₁-C₁₂-alkyl, C₃-C₈-cycloalkyl or halo-C₁-C₆-alkyl,

R⁶ is hydrogen, C₁-C₁₂-alkyl, C₃-C₈-cycloalkyl, halo-C₁-C₆-alkyl, aryl,or —NR⁷R⁸,

R⁷ and R⁸, independently of one another, are hydrogen, —SO₂R⁶, —COR⁶,aryl, C₃-C₈-cycloalkyl, C₁-C₁₂-alkyl, halo-C₁-C₁₂-alkyl, orC₁-C₁₂-alkoxy, whereby C₁-C₁₂-alkyl may be optionally substituted with—OR⁵ or —N(CH₃)₂, or R⁷ and R⁸ may also be chosen in such a way as toprovide a 3-8 membered cycloalkyl ring, preferably a 4-7 memberedcycloalkyl ring, more preferably a 5 or 6 membered cycloalkyl ring,which may optionally contain further heteroatoms, to such as nitrogen,oxygen or sulphur, and may be optionally substituted in one or moreplaces in the same way or differently with halogen, cyano, C₁-C₁₂-alkyl,C₁-C₁₂-alkoxy, halo-C₁-C₆-alkyl., ═O, —OR⁵ , COR⁶, —SR⁴, —SOR⁴ or—SO₂R⁶, and

as well as isomers, diastereoisomers, enantiomers, tautomers and saltsthereof.

In a further preferred embodiment:

X is CH,

W is hydrogen,

A, E and Q each are CH,

R¹ is

wherein R⁹ is hydrogen, halogen, C₁-C₁₂-alkyl, C₁-C₁₂-alkoxy,halo-C₁-C₆-alkyl, —COR⁶, —CO₂R⁶ or —NR⁷R⁸, whereby C₁-C₁₂-alkyl may besubstituted with —OR⁵ or —NR⁷R⁸ and R¹⁰ is hydrogen or halogen;

R² and R³ independently of one another, are C₁-C₂ alkyl optionallysubstituted with —OR⁵;

R⁴ is C₁-C₁₂-alkyl, C₃-C₈-cycloalkyl, aryl or heteroaryl,

R⁵ is hydrogen, C₁-C₁₂-alkyl, C₃-C₈-cycloalkyl or halo-C₁-C₆-alkyl,

R⁶ is hydrogen, C₁-C₁₂-alkyl, C₃-C₈-cycloalkyl, halo-C₁-C₆-alkyl, aryl,or —NR⁷R⁸,

R⁷ and R⁸, independently of one another, are hydrogen, —SO₂R⁶, —COR⁶,aryl, C₃-C₈-cycloalkyl, C₁-C₁₂-alkyl, halo-C₁-C₁₂-alkyl, orC₁-C₁₂-alkoxy, whereby C₁-C₁₂-alkyl may be optionally substituted with—OR⁵ or —N(CH₃)₂, or R⁷ and R⁸ may also be chosen in such a way as toprovide a 3-8 membered cycloalkyl ring, preferably a 4-7 memberedcycloalkyl ring, more preferably a 5 or 6 membered cycloalkyl ring,which may optionally contain further heteroatoms, such as nitrogen,oxygen or sulphur, and may be optionally substituted in one or moreplaces in the same way or differently with halogen, cyano, C₁-C₁₂-alkyl,C₁-C₁₂-atkoxy, halo-C₁-C₆-alkyl, ═O, —OR⁵, COR⁶, —SR⁴, —SOR⁴ or —SO₂R⁶ ,and

as well as isomers, diastereoisomers, enantiomers, tautomers and saltsthereof.

In a more preferred embodiment:

X is CH,

W is hydrogen,

A, E and Q each are CH,

R¹ is

-   -   wherein R⁹ is hydrogen and R¹⁰ is hydrogen or halogen;

R² and R³, independently of one another, are C₁-C₂ alkyl optionallysubstituted with —OR⁵, and

as well as isomers, diastereoisomers, enantiomers, tautomers and saltsthereof.

In an even more preferred embodiment:

X is CH,

W is hydrogen,

A, E and Q each are CH,

R¹ is

-   -   wherein R⁹ is hydrogen, halogen, C₁-C₁₂-alkyl, C₁-C₁₂-alkoxy,        halo-C₁-C₆-alkyl, —COR⁶, —CO₂R⁶ or —N⁷N⁸, whereby C₁-C₁₂-alkyl        may be substituted with —OR⁵ or —NR⁷R⁸,

R² and R³, independently of one another are unsubstituted C₁-C₂ alkyl,and

as well as isomers, diastereoisomers, enantiomers, tautomers and saltsthereof.

In a more particularly preferred embodiment:

X is CH,

W is hydrogen,

A, E and Q each are CH,

R¹ is

-   -   wherein R⁹ is hydrogen,

R² and R³ are both unsubstituted C₁-C₂ alkyl, and

as well as isomers, diastereoisomers, enantiomers, tautomers and saltsthereof.

It is understood that any combination of the definitions given in theabove-mentioned embodiments is possible within the context of thepresent invention.

Some specific examples of compounds of the present invention include thefollowing:

2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(2-methyl-2H-indazol-6-yl)-benzamide

2-{[2-(3,3-diethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(2-methyl-2H-indazol-6-yl)-benzamide

2-({2-[3-(2-hydroxy-ethyl)-3-methyl-ureido]-pyridin-4-ylmethyl}-amino)-N-(2-methyl-2H-indazol-6-yl)-benzamide

2-({2-[3-(2-methoxy-ethyl)-3-methyl-ureido]-pyridin-4-ylmethyl}-amino)-N-(2-methyl-21-indazol-6-yl)-benzamide

2-{[2-(3-ethyl-3-methyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(2-methyl-2H-indazol-6-yl)-benzamide

2-{([2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(4-fluoro-2-methyl-2H-indazol-6-yl)-benzamide

2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(7-methoxy-isoquinolin-3-yl)-benzamide

6-(2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-benzoylamino)-2-methyl-2H-indazole-3-carboxylicacid methyl ester

2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(2-methyl-2H-benzotriazol-5-yl)-benzamide

2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(1-methyl-2-oxo-1,2-dihydro-quinolin-6-yl)-benzamide

2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(2-methyl-2H-indazol-7-yl)-benzamide

2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(1-methyl-3a,7a-dihydro-1H-indazol-4-yl)-benzamide

2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(5-fluoro-2-methyl-2H-indazol-4-yl)-benzamide

2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(6-fluoro-2-methyl-2H-indazol-7-yl)-benzamide

6-(2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-benzoylamino)-1-methyl-1H-indazole-3-carboxylicacid methyl ester

to2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(3-hydroxymethyl-1-methyl-1H-indazol-6-yl)-benzamide

N-(3,6-difluoro-quinolin-2-yl)-2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-benzamide

2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(3-sulfamoyl-phenyl)-benzamide

N-(2,3-dimethyl-2H-indazol-6-yl)-2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-benzamide

2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(3-methoxymethyl-2-methyl-2H-indazol-6-yl)-benzamide

2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(3-methoxymethyl-1-methyl-1H-indazol-6-yl)-benzamide

6-(2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-benzoylamino)-1-methyl-1H-indazole-3-carboxylicacid methylamide

2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(6-fluoro-1-methyl-1H-indazol-5-yl)-benzamide

2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(6-fluoro-2-methyl-2H-indazol-5-yl)-benzamide

2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(5-fluoro-1-methyl-1H-indazol-4-yl)-benzamide

2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-quinolin-3-yl-benzamide

2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(3-fluoro-6-methoxy-quinolin-2-yl)-benzamide

2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(3-methyl-3H-benzoimidazol-5-yl)-benzamide

2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(1-methyl-1H-benzoimidazol-5-yl)-benzamide

2-{[2-(3,3-Dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(3-methanesulfonyl-phenyl)-benzamide

2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-6-fluoro-N-(2-methyl-2H-indazol-6-yl)-benzamide

The compounds of formula (I) can be used as pharmaceutical agents basedon their inhibitory activity relative to the phosphorylation of VEGFreceptors. Based on their profile of action, the compounds according tothe invention are suitable for preventing or treating diseases that arecaused or promoted by persistent angiogenesis.

Since the compounds of formula (I) are identified as inhibitors of thetyrosine kinases VEGFR-1 and VEGFR-2, they are suitable in particularfor preventing or treating those diseases that are caused or promoted bypersistent angiogenesis that is triggered via the VEGF receptor or by anincrease in vascular permeability.

The present invention also provides the use of the compounds of formula(I) as inhibitors of the tyrosine kinases VEGFR-1 and VEGFR-2, or KDRand FLT.

The term “diseases that are caused or promoted by persistentangiogenesis” relates especially to diseases such as tumor or metastasisgrowth, psoriasis, Kaposi's sarcoma, restenosis, such as, e.g.,stent-induced restenosis, endometriosis, Crohn's disease, Hodgkin'sdisease, leukemia; arthritis, such as rheumatoid arthritis, hemangioma,angiofibroma; eye diseases, such as diabetic retinopathy, neovascularglaucoma; corneal transplants; renal diseases, such asglomerulonephritis, diabetic nephropathy, malignant nephrosclerosis,thrombic microangiopathic syndrome, transplant rejections andglomerulopathy; fibrotic diseases, such as cirrhosis of the liver,mesangial cell proliferative diseases, arteriosclerosis, injuries tonerve tissue, and for inhibiting the reocclusion of vessels afterballoon catheter treatment, in vascular prosthetics or after mechanicaldevices are used to keep vessels open, such as, e.g., stents, asimmunosuppressive agents, for supporting scar-free healing, in senilekeratosis, in contact dermatitis, and in asthma.

In treating injuries to nerve tissue, quick scar formation on the injurysites can be prevented with the compounds according to the invention,i.e., scar formation is prevented from occurring before the axonsreconnect. A reconstruction of the nerve compounds can thus befacilitated.

The formation of ascites in patients, especially patients suffering fromtumors caused by metastases, can also be suppressed with the compoundsaccording to the invention. VEGF-induced oedemas can also be suppressed.

By a treatment with the compounds of formula (I), not only a reductionof the size of metastases but also a reduction of the number ofmetastases can be achieved.

Lymphangiogenesis plays an important role in lymphogenic metastasis(Karpanen, T. et al., Cancer Res. 2001 Mar. 1, 61(5): 1786-90, Veikkola,T., et al., EMBO J. 2001, Mar. 15; 20 (6): 1223-31).

The compounds of formula (I) also show excellent action as VEGFR kinase3 inhibitors and are, therefore, also suitable as effective inhibitorsof lymphangiogenesis.

The compounds of formula (I) are thus effective in the prevention ortreatment of diseases that are associated with excessivelymphangiogenesis, such as lymphedema, lymphangiectasia, lymphangioma,and lymphangiosarcoma but also asthma. Lymphatic growth around tumorsmay facilitate metastatic spread of malignant cells that ultimately killthe patient. This process can be effectively hindered by the compoundsof this invention. Thus the compounds are not only effective ininhibiting metastasis growth, but can also be effective in reducing thenumber of metastases.

This invention also provides the use of the compounds of formula (I) asinhibitors of the tyrosine kinase VEGFR-3 (FLT-4).

A further object of this invention is also a pharmaceutical agent forpreventing or treating diseases that are associated with excessivelymphangiogenesis, such as metastasis growth, lymphedema,lymphangiectasia, lymphangioma, and lymphangiosarcoma but also asthma.

Furthermore, the invention relates to the use of the compounds ofgeneral formula (I) for the preparation of a pharmaceutical agent foruse in or for the prevention or treatment of tumor or metastasis growth,psoriasis, Kaposi's sarcoma, restenosis, such as, e.g., stent-inducedrestenosis, endometriosis, Crohn's disease, Hodgkin's disease, leukemia;arthritis, such as rheumatoid arthritis, hemangioma, angiofibroma; eyediseases, such as diabetic retinopathy, neovascular glaucoma; cornealtransplants; renal diseases, such as glomerulonephritis, diabeticnephropathy, malignant nephrosclerosis, thrombic microangiopathicsyndrome, transplant rejections and glomerulopathy; fibrotic diseases,such as cirrhosis of the liver, mesangial cell proliferative diseases,arteriosclerosis, injuries to nerve tissue, and for inhibiting thereocclusion of is vessels after balloon catheter treatment, in vascularprosthetics or after mechanical devices are used to keep vessels open,such as, e.g., stents, as immunosuppressive agents, for supportingscar-free healing, in senile keratosis, in contact dermatitis, and alsoin asthma.

To use the compounds of formula (I) as pharmaceutical agents, the latterare brought into the form of a pharmaceutical preparation, which inaddition to the active ingredient for enteral or parenteraladministration contains suitable pharmaceutical, organic or inorganicinert carrier materials, such as, for example, water, gelatin, gumarabic, lactose, starch, magnesium stearate, talc, vegetable oils,polyalkylene glycols, etc. The pharmaceutical preparations can bepresent in solid form, for example as tablets, coated tablets,suppositories, capsules or in liquid form, for example as solutions,suspensions or emulsions. They also can contain, moreover, adjuvantssuch as preservatives, stabilizers, wetting agents or emulsifiers, saltsfor changing osmotic pressure or buffers.

For parenteral administration, especially injection solutions orsuspensions, especially aqueous solutions of the active compounds inpolyhydroxyethoxylated castor oil, are suitable.

As carrier systems, surface-active adjuvants such as salts of bile acidsor animal or plant phospholipids, but also mixtures thereof as well asliposomes or components thereof can also be used.

For oral administration, especially tablets, coated tablets or capsuleswith talc and/or hydrocarbon vehicles or binders, such as for example,lactose, corn starch or potato starch, are suitable. The administrationcan also be carried out in liquid form, such as, for example, as juice,to which optionally a sweetener or, if necessary, one or more flavouringsubstances, is added.

The dosage of the active ingredients can vary depending on the method ofadministration, age and weight of the patient, type and severity of thedisease to be treated and similar factors. The daily dose is 0.5-1000mg, preferably 50-200 mg, whereby the dose can be given as a single doseto be administered once or divided into 2 or more daily doses.

A further object of this invention is therefore a pharmaceutical agentcomprising a compound of formula (I) in combination with at least onepharmaceutically acceptable carrier or excipient.

Compounds of formula (I) are obtained, in that a compound of generalformula (II):

in which A, E, Q, W, X and R¹ are defined supra as for general formula(I) and M stands for halogen, is (i) first converted to an amine andthen, by reaction with a carbamoyl chloride of formula ClCONR²R³ inwhich R² and R³ are defined supra as for general formula (I), isconverted to a urea of general formula (I), or (ii) reacted with a ureaof general formula H₂NCONR²R³ in which R² and R³ are defined supra asfor general formula (I), or (iii) first converted to an amine, thenconverted to a compound of formula (I) by first reacting with a compoundof formula ClCO₂Ph and then reacting with a compound of formula HNR²R³,wherein R² and R³ are defined supra as for general formula (I); or acompound of general formula (III) in which A, E, Q, W, X, R², and R³ aredefined supra as for general formula (I) and R^(Y) stands for H orC₁-C₆-alkyl, is reacted with an amine of general formula R¹NH₂ in whichR¹ is defined supra as for general is formula (I),

There are many methods known to the person skilled in the art in theliterature for amide formation. For example, it is possible to startfrom the corresponding ester. The ester may be reacted according to J.Org. Chem. 1995, 8414 with trimethylaluminium and the correspondingamine in solvents such as toluene or 1,2-dichloroethane, at temperaturesof 0° C. to the boiling point of the solvent. If the molecule containstwo ester groups, both are converted into the same amide. Instead oftrimethylaluminium, sodium hexamethyldisilazide can also be used.

For amide formation, however, all processes that are known to the personskilled in the art from peptide chemistry are also available. Forexample, the io corresponding acid, obtained from the correspondingester by saponification, can be reacted with the amine in aprotic polarsolvents, such as, for example, dimethylformamide, via an activated acidderivative, obtainable, for example, with hydroxybenzotriazote and acarbodiimide, such as, for example, diisopropylcarbodiimide, attemperatures of between 0° C. and the boiling point of the solvent,preferably at 80° C., or else with preformed reagents, such as, forexample, HATU (O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate) (Chem. Comm. 1994, 201), at temperatures of between0° C. and the boiling point of the solvent, preferably at roomtemperature. The addition of a base such as N-methylmorpholine, forexample, is necessary. Amide formation, may also be accomplished via theacid halide, mixed acid anhydride, imidazolide or azide.

The ureas of aryl- or heteroaryl amines may be prepared by a variety ofliterature known methods, known to the person skilled in the art. Forexample, they may be prepared by the reaction of aryl- or heteroarylamines with isocyanates, the reaction of amines with aryl- orheteroaryl-carbamates such as aryl- or heteroaryl-phenoxycarbamates, orthe reaction of aryl- or heteroaryl amines with appropriatelysubstituted carbamoyl chlorides, or the reaction of an aryl- orheteroaryl-halide with ureas under the influence of metal catalysis.

For example, the ureas of aminopyridines may be prepared by reacting aurea with halopyridines, whereby chloro and bromopyridines arepreferred, under the catalytic influence of metal complexes, forexample, palladium- or copper complexes. In the case of copper complexesthe use of stoichiometric amounts of the copper complexes may beadvantageous for the reaction outcome.

Suitable copper salts for the reaction are copper (I) or copper (II)salts whereby copper (I) salts such as, for example, copper (I) oxide orcopper (I) iodide, are preferred. In the case of copper (I) iodide theaddition of an additive such as, for example, ethylenediamine isnecessary. Suitable solvents for this copper promoted coupling aredioxane or dimethylformamide, at temperatures upto the boiling point ofthe solvents, whereby 120° C. is preferred. Addition of a base is alsonecessary, such as potassium phosphate or caesium carbonate. In the caseof palladium catalysis, palladium complexes such astris-(dibenzylideneacetone)-dipalladium(0) maybe employed. Suitablesolvents for is the reaction are toluene, dioxane or dimethylformamide,whereby mixtures of solvents may also be advantageous for the reaction,at temperatures from room temperature to the boiling points of thesolvents, whereby 110° C. is preferred. A co-ligand such as BINAP, DPPFor xantphos is also employed. A base is also required, suitable basesfor the reaction are for example, cesium carbonate, potassium phosphateor sodium tert-butoxide.

The required urea starting materials for the above copper or palladiumpromoted coupling, may in turn be prepared from the reaction of thecorresponding amines with the corresponding isocyanates. Solvents suchas for example dichloromethane, or isopropylalcohol may be employed attemperatures from 0° C. to the boiling points of the solvents, wherebyroom temperature is preferred.

Methods for the preparation of substituted or unsubstituted6-aminoindazoles are well known to the person skilled in the art, in theliterature. They may be obtained from the reduction of the correspondingnitroindazoles via catalytic hydrogenation or other well known reductionmethods. N-alkylation of substituted nitroindazoles may be accomplishedwith a variety of literature known alkylating agents. For example,methylation of N-1 or N-2 of a suitably functionalised 6-nitroindazolemay be accomplished by for example treatment with a base, preferablyCs₂CO₃ or NaH, and a methyl halide, preferably methyl iodide in asuitable solvent such as N,N-dimethylformamide, at temperatures rangingfrom 0° C. to 50° C., whereby 50° C. is preferred.3-Substituted-6-nitroindazoles may be prepared by a variety of methods.For example alkyl substituents may be introduced in the 3-position byway of standard Suzuki reactions between an appropriate 3-haloindazole,whereby the appropriate 3-iodoindazoles are preferred, and an alkylboronic acid, whereby the trialkylboraxines may also be employed.N-protection of the indazole may be advantageous for the reaction.6-Nitroindazole-3-carboxylic acid provides a suitable starting materialfor ester, amide, hydroxymethyl and alkoxymethyl substitution in the3-position of 6-nitroindazole, via well known transformations such astransesterification, amide coupling, reduction, or reduction followed byalkylation. 6-Nitroindazole-3-carbaldehyde (prepared by the reaction ofcommercial 6-nitroindole with NaNO₂ in the presence of dilute aqueoushydrochloric acid according to J. Med. Chem. 2001, 44, 7, 1021) providesa useful precursor to 6-nitroindazole-3-carboxylic acid via well knownoxidation methods. In turn 6-nitroindazote-3-carbaldehyde may also beconverted to 3-hydroxymethyl-6-nitroindazole,3-alkoxymethyl-6-nitroindazole, or 3-aminomethyl-6-nitroindazolederivatives by equally standard transformations such as reduction,reduction followed by alkylation, or reductive amination. Such standardtransformations may also be applied to the synthesis of othersubstituted aminoindazoles. A variety of substituted nitroindazoles arecommercially available, however they may be readily synthesised via thereaction of a suitable 2-amino-nitrotoluene derivative with, forexample, NaNO₂ and aqueous hydrochloric acid. if required, the nitrogroup may be introduced after the cyclisation reaction of a suitable2-aminotoluene derivative by standard nitration chemistry.

The preparation of N-alkylated-aminobenzimidazoles may be accomplishedfrom the corresponding N-alkylated-nitrobenzimidazotes via standardreduction chemistry. Alkylation of a suitable functionalisednitrobenzimidazole, for example with an alkyl halide and a base,furnishes N1- and N3-alkylated-nitrobenzimidazoles, which may beseparated and isolated in pure form by standard purification techniques.For example, 6-amino-1-methyl-benzimidazole may be produced by thereaction of commercial 5-nitrobenzimidazole with Mel and Cs₂CO₃ in DMFfollowed by purification (of the resulting mixture of 5- and6-nitro-1-methyl-benzimidazoles) and hydrogenation in the presence of10% Pd on charcoal. Similarly, the preparation ofN-alkylated-aminobenzotriazoles may also be accomplished from thecorresponding nitrobenzotriazoles. Alkylation of a suitablefunctionalised nitrobenzotriazole, for example with an alkyl halide anda base, furnishes N1-, N2- and N3-alkylated-nitrobenzotriazoles, whichmay be separated and isolated in pure form by standard purificationtechniques. Standard reduction chemistry furnishes the correspondingaminobenzotriazoles. For example, 5-amino-2-methyl-benzotriazole may beprepared according to a literature procedure (Eur. J. Med. Chem. 1992,27, 161-166).

The preparation of 3-aminoisoquinolines which are substituted in the7-position, may be accomplished via the corresponding3-amino-1-bromo-7-substituted isoquinoline by way of reductivedehalogenation. 3-amino-1-bromo-7-substituted isoquinolines may in turnbe prepared by the reaction of a suitable2-cyano-4-substituted-benzeneacetonitrile with HBr in acetic acid. Forexample, 3-amino-7-methoxyisoquinoline may be prepared in two steps (HBrmediated cyclisation followed by reductive dehalogenation) from2-cyano-4-methoxy-benzeneacetonitrile, which may be prepared accordingto a literature procedure (Bull. Chem. Soc. Jpn. 1980, 53, 10,2885-2890).

1-Alkyl-6-amino-quinolin-2-ones may be prepared by known methods. Forexample, 6-amino-2-methyl-quinolin-2-one may be prepared according to aliterature procedure (J. Chem. Research, Synopses, 1997, 310-311).

2-Amino-3,6-disubstituted quinolines may be prepared by a number ofprocedures. For example, the reaction of the lithium salt (generatedwith a base such as lithium diisopropylamide) of a suitably substitutedcyanomethyl-dialkylphosphonate with a suitably substituted2-nitrobenzaldehyde derivative in a suitable solvent, such as THF,furnishes a suitable acrylonitrile derivative which may be cyclised tothe desired 2-amino-3,6-disubstituted quinoline by treating with asuitable reducing agent, such as iron in acetic acid.

The compounds of the general formulae II and III:

in which A, E, Q, W, R¹, R² and R³, are defined in the same way as forthe general formula (I), M is halogen and R^(y) is H or C₁-C₆-alkyl,provide valuable intermediates for the preparation of the inventivecompounds of general formula (I) and, are therefore also objects of theinvention. The use of compounds of formula (II) and (III) in theproduction of a compound of formula (I), as well as the processdescribed above using these compounds in the production of a compound offormula (I) are also objects of the invention.

EXAMPLES Production of the Compounds According to the Invention

The following examples explain the production of the compounds accordingto the invention without the scope of the claimed compounds beinglimited to these examples.

Abbreviations

The following abbreviations used in the invention have the followingmeanings:

Brine saturated aqueous sodium chloride solution

Cl+ chemical ionisation (NH₃)

DCE 1,2-dichloroethane

DMF N,N-dimethyl formamide

d₆-DMSO d₆-dimethylsulfoxide

d doublet

dd doublet of doublets

ES+ positive mode electrospray ionisation

EtOAc ethyl acetate

EtOH ethanol

1H-NMR proton nuclear magnetic resonance spectroscopy: chemical shifts(□) are given in ppm.

Hex n-hexane

LC-ES+ liquid chromatography/positive mode electrospray ionisation

LDA Lithium diisopropylamide

MeOH methanol

m multiplet

Mp. melting point

MS mass spectrometry

m/z mass/charge ratio

Pd₂dba₃ tris-(dibenzylideneacetone)-dipalladium(0)-chloroform complex

rt room temperature

RT retention time (LC)

s singlet

THF tetrahydrofuran

t triplet

Xantphos 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene

Example 1.0 Preparation of2{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(2-methyl-2H-indazol-6-yl)-benzamide

2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(2-methyl-2H-indazol-6-yl)-benzamide(110 mg, 0.25 mmol, prepared as detailed infra in Example 4A) and1,1-dimethylurea (114 mg, 1.3 mmol) were suspended in dioxane (3 mL)under a nitrogen atmosphere and treated consecutively with DMF (1 mL),cesium carbonate (98 mg, 0.3 mmol), Pd₂dba₃ (5 mg, 0.005 mmol) andXantphos (9 mg, 0.015 mmol). The reaction mixture was flushed withnitrogen and heated for 5 hours at 110° C. (bath temperature). Oncooling the reaction was concentrated in vacua. The residue waspartitioned between CH₂Cl₂ and water. The organic phase was washed withbrine, dried, filtered and concentrated in vacuo. The residue waspurified by chromatography on Isolute® flash silica gel (Separtis)

(Gradient elution: 100% CH₂Cl₂ to CH₂Cl₂/EtOH 95:5) to give2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(2-methyl-2H-indazol-6-yl)-benzamide(79 mg, 71%) as a solid; 1H-NMR (300 MHz, d₆-DMSO) 10.15 (1H, s), 8.80(1H, s), 8.25 (1H, s), 8.13 (1H, d), 8.10 (1H, s), 7.95 (1H, t), 7.82(1H, s), 7.72 (1H, d), 7.63 (1H, d), 7.22-7.32 (2H, m), 6.95 (1H, d),6.68 (1H, t), 6.54 (1H, d), 4.45 (2H, d), 4.13 (3H, s), 2.91 (6H, s);m/z (ES+) 444 [M+H]⁺, 223; Mp. 184° C.

The following compounds were prepared in analogy from2-[(2-bromo-pyridin-4-ylmethyl)-amino]-N-(2-methyl-2H-indazol-6-yl)-benzamideand the corresponding urea:

Example Nr. R² R³ MW Mp. [° C.] or MS (m/z) 1.1 —CH₂CH₃ —CH₂CH₃ 471.57Foam (ES+) 472 [M + H]⁺, 237 1.2 —CH₃ —CH₂CH₂OH 473.54 Foam (ES+) 474[M + H]⁺ 1.3 —CH₃ —CH₂CH₂OCH₃ 487.57 Mp. 174 1.4 —CH₃ —CH₂CH₃ 457.54Foam (ES+) 458 [M + H]⁺, 230

The following compounds were prepared in analogy from the corresponding2-bromopyridine intermediate and 1,1-dimethylurea.

Example Mp. [° C.] or Nr. R¹ MW MS (m/z) 1.5

461.48 Foam (ES+) 462 [M + H]⁺, 227, 222 1.6

470.54 Foam (ES+) 471 [M + H]⁺, 236

Example 2.0 Preparation of6-(2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-benzoylamino)-2-methyl-2H-indazole-3-carboxylicacid methyl ester

2-{[2-(3,3-Dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-benzoic acid (112mg, 0.35 mmol), 6-amino-2-methyl-2H-indazole-3-carboxylic acid methylester (62 mg, 0.3 mmol), N-methylmorpholine (0.09 mL, 0.82 mmol) andHATU (152 mg, 0.4 mmol) were suspended in dry DMF (3 mL) and stirred atrt overnight. The reaction mixture was concentrated in vacuo and theresidue partitioned between dichloromethane.The organic phase was washedconsecutively with saturated aqueous sodium hydrogencarbonate solution,water and brine, dried and concentrated in vacuo. The residue waspurified by chromatography on Isolute® flash silica get (Separtis)(Gradient elution: 100% CH₂Cl₂ to CH₂Cl₂/EtOH 9:1) to give6-(2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-benzoylamino)-2-methyl-2H-indazole-3-carboxylicacid methyl ester (53 mg, 35%) as a solid; 1H-NMR (300 MHz, d₆-DMSO)10.30 (1H, s), 8.79 (1H, s), 8.30 (1H, m), 8.15 (1H, d), 7.92-7.99 (2H,m), 7.82 (1H, s), 7.75 (1H, dd), 7.62 (1H, o dd), 7.25-7.29 (1H, m),6.93-6.96 (1H, m), 6.68 (1H, t), 6.55 (1H, d), 4.45(2H, d), 4.41 (3H,s), 3.99 (3H, s), 2.92 (6H, s); m/z (ES+) 502 [M+H]⁺.

The following compounds were prepared in analogy from2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ytmethyl]-amino}-benzoic acid andthe corresponding amine:

Example Mp. [° C.] or Nr. R¹ MW MS (m/z) 2.1

444.50 Mp. 190.6 2.2

470.54 (ES+) 471 [M + H]⁺, 236 2.3

443.51 Foam (ES+) 444 [M + H]⁺, 223 2.4

443.51 Foam (ES+) 444 [M + H]⁺ 2.5

461.50 Foam (ES+) 462 [M + H]⁺, 343, 252 2.6

461.50 Foam (ES+) 462 [M + H]⁺, 232 2.7

501.54 Foam (ES+) 502 [M + H]⁺ 2.8

473.53 Foam (ES+) 474 [M + H]⁺ 2.9

476.48 Mp. 208 2.10

468.54 Resin (ES+) 469 [M + H]⁺, 342

Example 3.0 Preparation ofN-(2,3-dimethyl-2H-indazol-6-yl)-2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-benzamide

To a stirred solution of 2,3-dimethyl-2H-indazol-6-ylamine (60 mg, 0.34mmol) in DCE (1.5 mL) at 0° C., under nitrogen, was addedtrimethylaluminium (2M in toluene, 0.35 mL, 0.7 mmol), followed by asolution of2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethy]-amino}-benzoic acidmethyl ester (111 mg, 0.34 mmol) in DCE (1.5 mL). The reaction washeated at 100° C. (bath temperature) for 5 hours. On cooling thereaction was poured onto saturated aqueous sodium hydrogencarbonatesolution and diluted with dichloromethane. The mixture was stirred for15 minutes before filtering through Celite®. The organic phase waswashed with water and brine, dried, and concentrated in vacuo. Theresidue was purified by repeated chromatography on Isolute® flash silicagel (Separtis) (Gradient elution: 100% CH₂CL₂ to CH₂Cl₂/EtOH 95:5) togive N-(2,3-dimethyl-2H-indazol-6-yl)-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-benzamide (23 mg, 15%) as a solid; 1H-NMR(300 MHz, d₆-DMSO) 10.10 (1H, s), 8.79 (1H, s), 8.15 (1H, d), 8.00 (1H,s), 7.95 (1H, t), 7.82 (1H, s), 7.70-7.73 (1H, m), 7.60 (1H, d),7.22-7.29 (2H, m), 6.93-6.95 (1H, m), 6.67 (1H, t), 6.53 (1H, d), 4.45(2H, d), 4.01 (3H, s), 2.91 (6H, s), 2.59 (3H, s); m/z (ES+) 458 [M+H]⁺,230.

The following compounds were prepared in analogy from2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyt]-amino}-benzoic acidmethyl ester and the corresponding amine:

Example Mp. [C.] or Nr. R¹ MW MS (m/z) 3.1

487.56 Foam (ES+) 488 [M + H]⁺, 245 3.2

487.56 Foam (ES+) 488 [M + H]⁺, 383, 247 3.3

500.56 Foam (ES+) 501 [M + H]⁺ 3.4

461.50 Foam (ES+) 462 [M + H]⁺ 3.5

461.50 Foam (ES+) 462 [M + H]⁺, 417 3.6

461.50 Foam (ES+) 462 [M + H]⁺ 3.7

440.51 Foam (ES+) 441 [M +H]⁺, 396, 221, 219 3.8

488.52 Mp. 211.6 3.9

443.51 Foam (ES+) 444 [M + H]⁺, 399, 222 3.10

443.51 Foam (ES+) 444 [M + H]⁺, 399, 223, 221 3.11

467.55 Foam (ES+) 468 [M + H]⁺

Example 4.0 Preparation of2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-6-fluoro-N-(2-methyl-2H-indazol-6-yl)-benzamide

2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-6-fluoro-N-(2-methyl-2H-indazol-6-yl)-benzamide(227 mg, 0.5 mmol) was suspended in dioxane (4 mL) and treated ioconsecutively with DMF (1.6 mL), Pd₂dba₃ (13 mg, 0.013 mmol), Xantphos(18 mg, 0.031 mmol), cesium carbonate (193 mg, 0.59 mmol) and1,1-dimethylurea (232 mg, 2.63 mmol). The reaction mixture was placedunder an argon atmosphere and heated for 3 hours at 110° C. (bathtemperature). On cooling the reaction was partitioned between EtOAc andwater. The organic phase was dried and concentrated in vacuo. Theresidue was purified by chromatography on Isolute® Flash silica gel(Separtis) (Gradient elution: 100% CH₂Cl₂ to CH₂Cl₂/EtOH 9:1) to give2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-6-fluoro-N-(2-methyl-2H-indazol-6-yl)-benzamide(93 mg, 40%) as a resin. Further purification was accomplished bypreparative reverse phase HPLC [Column: Kromasil C8 5μ, 125×20 mm.Eluant: 38% CH₃CN in H₂O (containing 0.2% NH₃) to 95% CH₃CN in H₂O(containing 0.2% NH₃)]; 1H-NMR (300 MHz, d₆-DMSO) 10.43 (1H, s), 8.77(1H, s), 8.26 (1H, s), 8.23 (1H, s), 8.13 (1H, d), 7.80 (1H, s), 7.64(1H, d), 7.13-7.25 (2H, m), 6.93 (1H, d), 6.73 (1H, t), 6.48 (1H, t),6.29 (1H, d), 4.40 (2H, d), 4.14 (3H, s), 2.92 (6H, s); m/z (ES+) 462[M+H]⁺.

Production of Starting and Intermediate Compounds

If the production of the intermediate compounds is not described, thelatter are known, commerically available, or can be produced analogouslyto known compounds or processes that are described here or inWO2004/013102. Particularly, the intermediate compound2-[(2-bromopyridin-4-yl-methyl)-amino]-N-(2-methyl-2H-indazol-6-yl)-benzamideis prepared as is published in WO 2004/013102, which is reiteratedherein as Example 4a:

Example 4A Step 1: Production of2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-benzoic Acid Methyl Ester

6.04 g (40 mmol) of anthranilic acid methyl ester in 600 ml of methanolis mixed with 3.2 ml of acetic acid and 7.4 g (40 mmol) of2-bromopyridine-4-carbaldehyde and stirred overnight at 40° C. 3.8 g (60mmol) of sodium cyanoborohydride is added thereto and stirred overnightat 40° C. 3.8 g (60 mmol) of sodium cyanoborohydride is added again andstirred over the weekend at 40° C. It is mixed with water and largelyconcentrated by evaporation. The aqueous phase is extracted with ethylacetate, and the combined organic phases are dried, filtered andconcentrated by evaporation. The crude product is chromatographed onsilica gel with a gradient that consists of hexane and hexane/ethylacetate 1:3 and hexane/ethyl acetate 1:1 as an eluant. 10.0 g (78% oftheory) of 2-[(2-bromo-pyridin-4-ylmethyl)-amino]-benzoic acid methylester is obtained as a colorless oil.

Step 2 Production of 2-[(2-Bromo-pyridin-4-ylmethyl)-amino]benzoic Acid

10.0 g (31.2 mmol) of 2-[(2-bromo-pyridin-4-ylmethyl)-amino]-benzoicacid methyl ester is dissolved in 290 ml of ethanol and mixed with 31.2ml of 2 M sodium hydroxide solution. After having been stirred overnightat room temperature, the ethanol is drawn off, and the aqueous phase isshaken out with ethyl acetate. The aqueous phase is acidified withconcentrated hydrochloric acid. The precipitate that is formed issuctioned off and dried. 5.93 g (62%) of2-[(2-bromo-pyridin-4-ylmethyl)-amino]-benzoic acid accumulates in theform of a white solid.

Step 3: Production of2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(2-methyl-2H-indazol-6-yl)-benzamide

0.500 g (1.6 mmol) of 2-[(2-bromo-pyridin-4-ylmethyl)-amino]-benzoicacid, 0.471 g (3.2 mmol) of 2-methyl-2H-indazol-6-ylamine, 0.4 ml (3.68mmol) of N-methylmorpholine and 0.729 g (1.92 mmol) ofO-(7-azabenzotriazol-1-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate(HATU) in 25 ml of dimethylformamide are stirred for 16 hours at roomtemperature. The dimethylformamide is drawn off in an oil pump vacuum.The remaining residue is drawn off in saturated sodium bicarbonatesolution. It is extracted three times with ethyl acetate, and thecombined organic phases are dried, filtered and concentrated byevaporation. The residue is chromatographed on silica gel with agradient that consists of hexane:acetone=100:0 to 50:50 as an eluant.0.669 g (96% of theory) of2-[(2-bromo-pyridin-4-ylmethyl)-amino]-N-(2-methyl-2H-indazol-6-yl)-benzamideis obtained in the form of a beige foam.

Example 5.0 Preparation of2-[(2-bromo-pyridin-4-ylmethyl)-amino]-(4-fluoro-2-methyl-2H-indazol-7-yl)-benzamide

2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(4-fluoro-2-methyl-2H-indazol-7-yl)-benzamidewas prepared from 2-[(2-bromo-pyridin-4-ylmethyl)-amino]-benzoic acidmethyl ester and 7-amino-4-fluoro-2-methyl-2H-indazote in analogy to theprocedures detailed in Example 4A; 1H-NMR (300 MHz, d₆-DMSO) 9.86 (1H,s), 8.60 (1H, s), 8.32 (1H, d), 8.13 (1H, t), 7.83 (1H, d), 7.58-7.61(2H, m), 7.42 (1H, d), 7.30 (1H, t), 6.82 (1H, dd), 6.72 (1H, t), 6.59(1H, d), 4.52 (2H, d), 4.22 (3H, s); m/z (ES+) 454, 456 [M+H, Brisotopes]⁺.

Example 6.0 Preparation of2-[(2-bromo-pyridin-4-ylmethyl)-amino]-N-(7-methoxy-isoquinolin-3-yl)-benzamide

2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-N-(7-methoxy-isoquinolin-3-yl)benzamidewas prepared from 2-[(2-bromo-pyridin-4-ylmethyl)-amino]-benzoic acidmethyl ester and 3-amino-7-methoxyisoquinoline in analogy to theprocedures detailed in Example 4A ; 1H-NMR (300 MHz, d₆-DMSO) 10.62 (1H,s), 9.10 (1H, s), 8.51 (1H, s), 8.32 (1H, d), 8.11 (1H, t), 7.83-7.90(2H, m), 7.60 (1H, s), 7.50 (1H, m), 7.38-7.41 (2H, m), 7.27 (1H, t),6.66 (1H, t), 6.55 (1H, d), 4.54 (2H, d), 3.91 (3H, s).

Example 7.0 Preparation of2-[(2-bromo-pyridin-4-ylmethyl)-amino]-6-fluoro-N-(2-methyl-2H-indazol-6-yl)-benzamide

2-[(2-Bromo-pyridin-4-ylmethyl)-amino]-6-fluoro-N-(2-methyl-2H-indazol-6-yl)-benzamidewas prepared from methyl 2-amino-6-fluorobenzoate in analogy to theprocedures detailed in Example 4A ; 1H-NMR (300 MHz, d₆-DMSO) 10.51 (1H,s), 8.31 (1H, d), 8.26-8.28 (2H, m), 7.65 (1H, d), 7.59 (1H, s), 7.40(1H, d), 7.13-7.25 (2H, m), 6.73 (1H, t), 6.50 (1H, t), 6.29 (1H, d),4.47 (2H, d), 4.13 (3H, s).

Example 8.0 Preparation of 1-(2-methoxy-ethyl)-1-methyl-urea

To a stirred solution of N-(2-methoxyethyl)-methylamine (1 g, 11.21mmol) in isopropanol (30 mL) at rt was added trimethylsilytisocyanate(2.2 mL, 15.5 mmol) and the resulting solution stirred overnight. Thereaction was concentrated in io vacuo to give1-(2-methoxy-ethyl)-1-methyl-urea (1.69 g, quant.); 1H-NMR (300 MHz,d₆-DMSO) 5.75 (2H, s), 3.27-3.43 (4H, m), 3.25 (3H, s), 2.79 (3H, s).

The following Examples detail the biological activity and use of thecompounds of the invention without the scope of the claimed compoundsbeing limited to these examples.

KDR Kinase Inhibition

Kinase activity was measured with a GST-kinase domain fusion constructof the KDR kinase according to the following protocol to obtainconcentration response curves. Components were added into amicrotiterplate in the following sequence: 10 μl of inhibitor inthreefold final concentration [3% DMSO in buffer (40 mM TrisCl pH 7.5; 1mM DTT, 1 mM MnCl₂, 10 mM MgCl₂, 2.5 Promille Polyethyleneglycol 20000)]and 10 μl of substrate mixture [24 μM ATP, 24 μg/ml poly(Glu₄Tyr) inbuffer, specific activity approx. 500 cpm/pmol ³²P-□ATP]. Reaction wasstarted by adding 10 μl of enzyme preparation diluted appropriately inbuffer that contains 10 μM vanadate. After incubation for exactly 10 minthe reaction was stopped by adding of 10 μl stop solution (250 mM EDTA).10 μl of the reaction mixture were transferred to phosphocellulosefilters. The filters were washed in 0.1% phosphoric acid, dried beforemeltilex scintillator was applied (Wallac, Perkin-Elmer) and theradioactivity was counted.

VEGFR-3 Autophosphorylation

MVECs (1.5×10⁶/well) of a low passage number were plated on collagen-Gcoated 48 well plates in EBM complete medium (including EGM-2,BD-Clonetech). 5 h Later, medium was exchanged for EBM-2 without EGM-2but containing 0.2% BSA (EBM meager). 12 h later medium was removed, 250μl EBM-2 meager and the respective compound dilutions were added in 50μl EBM-2 meager. Solutions were carefully mixed and left for 5 min at 4°C. before the addition of 200 μl EBM-2 meager containing VEGF-C (finalconcentration in the assay is 5 nM; Reliatech, Braunschweig). Thesolution was then carefully mixed and incubated for 15 min at roomtemperature. The medium was removed and cells were washed twice withcold PBS/2mM vanadate. Cells were then lysed with 100 μl Duschl buffer[50 mM Hepes pH 7.2; 150 mM NaCl; 1 mM MgCl₂; 1.5% Triton X-100; 10 mMNa-Pyrophosphate; 100 mM Na-Fluoride; 10% glycerol+(freshly added beforethe experiment) 2 mM Orthovanadate and 1 tablet per 50 ml Complete(Roche # 1836145)]

For the ELISA, Moronic MaxiSorp—MTP plates (# 3204006 Zinser)—werecoated overnight at 4° C. with Flt-4 antibody (Flt-4 (C-20) # sc-321Santa Cruz); 1 μg/ml in coating buffer: Na₂CO₃ pH 9.6 100 μl/well).After 3× washing with washing buffer (0.1% Tween 20 in Na₂HPO₄ pH 7.4)the wells were incubated with 250 μl blocking buffer (Roti Block 1/10from Roth, Karlsruhe for 1 h at room temperature). 3×

Washing with washing buffer was followed by addition of cell lysates andincubation over night at 4° C. Then wells were washed 3×,anti-phosophotyrosine antibody coupled to HRP(16-105; UPSTATE; dilution1/20000 in TBST+3% Top Block # 37766, Fluka) was added and incubatedovernight at 4° C. Washing with washing buffer (6×) preceded theaddition of BM chemoluminescence ELISA reagent # 1582950 (Roche) andmeasurement of luminescence.

Cytochrome P450 Inhibition

The Cytochrome P450 isoenzyme inhibition was performed according to thepublication of Crespi et al. (Anal. Biochem., 1997, 248, 188-190) withuse of the baculovirus/insect cell-expressed, human Cytochrome P 450isoenzymes (2C9 and 2C19).

Selected results are presented in the following Table:

IC50 KDR-Kinase IC50 CYP IC50 CYP Example (VEGFR-2) (nM) 2C9 (μM) 2C19(μM) 3.30 10 0.9 1.7 from WO 04/13102 3.40 40 1.1 2.3 from WO 04/131023.41 27 5.7 1.5 from WO 04/13102 1.0 25 6.7 19 1.1 35 3.8 9.9 1.4 24 6.626 2.2 36 10 6.4

The advantages of the compounds of the invention compared to knowncompounds can be readily demonstrated by the above studies.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The preceding preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limitative ofthe remainder of the disclosure in any way whatsoever.

In the foregoing and in the examples, all temperatures are set forthuncorrected in degrees Celsius and, all parts and percentages are byweight, unless otherwise indicated.

The entire disclosures of all applications, patents and publications,cited herein and of corresponding European application No. 04090419,filed Nov. 3, 2004 and U.S. Provisional Application Ser. No. 60/626,914,filed Nov. 12, 2004, are incorporated by reference herein.

The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention and, withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

1-46. (canceled)
 47. A method for treating or preventing a diseaseassociated with persistent angiogenesis or a disease associated withexcessive lymphangiogenesis; for treating or preventing a tumor- ormetastases-growth; psoriasis; Karposi's sarcoma; restenosis;stent-induced restenosis; Crohn's disease; Hodgkin's disease; leukemia;arthritis; rheumatoid arthritis, hemangioma, angiofibroma;endometriosis; an eye disease; diabetic retinopathy, neovascularglaucoma; corneal transplants; a renal disease; glomerulonephritis,diabetic nephropathy, malignant nephrosclerosis, thromboticmicroangiopathic syndrome, a transplant rejections; glomerulopathy; afibrotic disease; cirrhosis of the liver; a mesangial cell proliferativedisease; arteriosclerosis; injuries to the nerve tissue, or forinhibiting the reocclusion of vessels after balloon catheter treatment;in vascular prosthetics or after a mechanical device is used to keep avessel open, or for supporting scar-free healing; senile keratosis;contact dermatitis; or asthma; for inhibiting VEGF receptor kinase 3 oflymphangiogenesis; for the prevention or treatment of a disease forwhich an inhibition of angiogenesis and/or lymphangiogenesis and/or theVEGF receptor kinases is beneficial; comprising administering to asubject in need thereof an effective amount of a compound of formula I

wherein: X is CH or N; W is hydrogen or fluorine; A, E and Q,independently of one another, are CH or N, wherein only a maximum of twonitrogen atoms are contained in the ring; R¹ is aryl or heteroaryl,which are optionally substituted in one or more places in the same wayor differently with halogen, hydroxy, C₁-C₁₂-alkyl, C₂-C₆-alkenyl,C₁-C₁₂-alkoxy, halo-C₁-C₆-alkyl, ═O, —SO₂R⁶, —OR⁵, —SOR⁴, —COR⁶, —CO₂R⁶or —NR⁷R⁸, wherein C₁-C₁₂-alkyl is optionally substituted with —OR⁵ or—NR⁷R⁸, with the proviso that when R² and R³ are both —CH₃, R¹ is notany one of the following:

R² and R³, independently of one another, are C₁-C₁₂ alkyl optionallysubstituted with —OR⁵; R⁴ is C₁-C₁₂-alkyl, C₃-C₈-cycloalkyl, aryl orheteroaryl; R⁵ is hydrogen, C₁-C₁₂-alkyl, C₃-C₈-cycloalkyl orhalo-C₁-C₆-alkyl; R⁶ is hydrogen, C₁-C₁₂-alkyl, C₃-C₈-cycloalkyl,halo-C₁-C₆-alkyl, aryl, or —NR⁷R⁸; and R⁷ and R⁸, independently of oneanother, are hydrogen, —SO₂R⁶, —COR⁶, aryl, C₃-C₈-cycloalkyl,C₁-C₁₂-alkyl, halo-C₁-C₁₂-alkyl, or C₁-C₁₂-alkoxy, wherein C₁-C₁₂-alkylis optionally substituted with —OR⁵ or —N(_(CH) ₃)₂, or R⁷ and R⁸provide a 3-8 membered cycloalkyl ring, which optionally contains one ormore further heteroatoms, and is optionally substituted in one or moreplaces in the same way or differently with halogen, cyano, C₁-C₁₂-alkyl,C₁-C₁₂-alkoxy, halo-C₁ ₁-C₆-alkyl, ═O, —OR⁵, COR⁶, —SR⁴, —SOR⁴ or—SO₂R⁶; or an isomer, diastereoisomer, enantiomer, tautomer or saltthereof.
 48. A method according to claim 47, which is for treating orpreventing a disease associated with persistent angiogenesis or adisease associated with excessive lymphangiogenesis.
 49. A methodaccording to claim 47, which is for treating or preventing a tumor- ormetastases-growth; psoriasis; Karposi's sarcoma; restenosis;stent-induced restenosis; Crohn's disease; Hodgkin's disease; leukemia;arthritis; rheumatoid arthritis, hemangioma, angiofibroma;endometriosis; an eye disease; diabetic retinopathy, neovascularglaucoma; corneal transplants; a renal disease; glomerulonephritis,diabetic nephropathy, malignant nephrosclerosis, thromboticmicroangiopathic syndrome, a transplant rejections; glomerulopathy; afibrotic disease; cirrhosis of the liver; a mesangial cell proliferativedisease; arteriosclerosis; injuries to the nerve tissue, or forinhibiting the reocclusion of vessels after balloon catheter treatment;in vascular prosthetics or after a mechanical device is used to keep avessel open, or for supporting scar-free healing; senile keratosis;contact dermatitis; or asthma.
 50. A method according to claim 47, whichis for inhibiting VEGF receptor kinase 3 of lymphangiogenesis.
 51. Amethod according to claim 47, which is for the prevention or treatmentof a disease for which an inhibition of angiogenesis and/orlymphangiogenesis and/or the VEGF receptor kinases is beneficial.
 52. Amethod according to claim 51, which is for inhibiting the tyrosinekinase VEGFR-1 or VEGFR-2.
 53. A method according to claim 47, whereinthe compound of formula I is2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(2-methyl-2H-indazol-6-yl)-benzamide2-{[2-(3,3-diethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(2-methyl-2H-indazol-6-yl)-benzamide2-({2-[3-(2-hydroxy-ethyl)-3-methyl-ureido]-pyridin-4-ylmethyl}-amino)-N-(2-methyl-2H-indazol-6-yl)-benzamide2-({2-[3-(2-methoxy-ethyl)-3-methyl-ureido]-pyridin-4-ylmethyl}-amino)-N-(2-methyl-2H-indazol-6-yl)-benzamide2-{[2-(3-ethyl-3-methyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(2-methyl-2H-indazol-6-yl)-benzamide2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(4-fluoro-2-methyl-2H-indazol-6-yl)-benzamide2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(7-methoxy-isoquinolin-3-yl)-benzamide6-(2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-benzoylamino)-2-methyl-2H-indazole-3-carboxylicacid methyl ester2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(2-methyl-2H-benzotriazol-5-yl)-benzamide2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(1-methyl-2-oxo-1,2-dihydro-quinolin-6-yl)-benzamide2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(2-methyl-2H-indazol-7-yl)-benzamide2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(1-methyl-3a,7a-dihydro-1H-indazol-4-yl)-benzamide2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(5-fluoro-2-methyl-2H-indazol-4-yl)-benzamide2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(6-fluoro-2-methyl-2H-indazol-7-yl)-benzamide6-(2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-benzoylamino)-1-methyl-1H-indazole-3-carboxylicacid methyl ester2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(3-hydroxymethyl-l-methyl-1H-indazol-6-yl)-benzamideN-(3,6-difluoro-quinolin-2-yl)-2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-benzamide2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(3-sulfamoyl-phenyl)-benzamideN-(2,3-dimethyl-2H-indazol-6-yl)-2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-benzamide2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(3-methoxymethyl-2-methyl-2H-indazol-6-yl)-benzamide2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(3-methoxymethyl-1-methyl-1H-indazol-6-yl)-benzamide6-(2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-benzoylamino)-1-methyl-1H-indazole-3-carboxylicacid methylamide2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(6-fluoro-l-methyl-1H-indazol-5-yl)-benzamide2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(6-fluoro-2-methyl-2H-indazol-5-yl)-benzamide2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(5-fluoro-l-methyl-1H-indazol-4-yl)-benzamide2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-quinolin-3-yl-benzamide2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(3-fluoro-6-methoxy-quinolin-2-yl)-benzamide2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(3-methyl-3H-benzoimidazol-5-yl)-benzamide2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(1-methyl-1H-benzoimidazol-5-yl)-benzamide2-{[2-(3,3-Dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(3-methanesulfonyl-phenyl)-benzamideor2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-6-fluoro-N-(2-methyl-2H-indazol-6-yl)-benzamideor an isomer, diastereoisomer, enantiomer, tautomer or salt thereof. 54.A method according to claim 47, wherein the compound of formula I is

wherein: X is CH; W is hydrogen or fluorine; A, E and Q, are CH; R¹ is2-methyl-2H-indazol-6-yl; R² and R³, independently of one another, areC₁-C₁₂ alkyl optionally substituted with —OR⁵; and or an isomer,diastereoisomer, enantiomer, tautomer or salt thereof.
 55. A methodaccording to claim 47, wherein the compound of formula I is2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(2-methyl-2H-indazol-6-yl)-benzamide2-{[2-(3,3-diethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(2-methyl-2H-indazol-6-yl)-benzamide2-({2-[3-(2-hydroxy-ethyl)-3-methyl-ureido]-pyridin-4-ylmethyl}-amino)-N-(2-methyl-2H-indazol-6-yl)-benzamide2-({2-[3-(2-methoxy-ethyl)-3-methyl-ureido]-pyridin-4-ylmethyl}-amino)-N-(2-methyl-2H-indazol-6-yl)-benzamide2-{[2-(3-ethyl-3-methyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(2-methyl-2H-indazol-6-yl)-benzamideor2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-6-fluoro-N-(2-methyl-2H-indazol-6-yl)-benzamideor an isomer, diastereoisomer, enantiomer, tautomer or salt thereof. 56.A method according to claim 47, wherein a compound of formula I or apharmaceutically acceptable salt thereof is administered.
 57. A methodaccording to claim 53, wherein a compound of formula I or apharmaceutically acceptable salt thereof is administered.
 58. A methodaccording to claim 47, wherein in the compound of formula I X is CH; Wis hydrogen or fluorine; A, E and Q, are CH; R¹ is2-methyl-2H-indazol-6-yl; R² and R³, independently of one another, areC₁-C₁₂ alkyl optionally substituted with —OR⁵.
 59. A method according toclaim 47, wherein in the compound of formula I W is fluorine.
 60. Amethod according to claim 47, wherein in the compound of formula I W ishydrogen.
 61. A method according to claim 47, wherein in the compound offormula I R² and R³ independently of one another, are C₁-C₁₂ alkyloptionally substituted with —OR⁵.
 62. A method according to claim 47,wherein in the compound of formula I R² and R³ are both —CH₃.
 63. Amethod according to claim 47, wherein in the compound of formula I R⁵ is—CH₃ or hydrogen.
 64. A method according to claim 47, wherein in thecompound of formula I R² and R³ independently of one another areunsubstituted C₁-C₂ alkyl.